salicylates and Diabetic-Angiopathies

OBJECTIVE Salsalate is a nonacetylated salicylate that lowers glucose levels in people with type 2 diabetes (T2D). Here we examined whether salsalate also lowered serum-protein-bound levels of early and advanced glycation end products (AGEs) that have been implicated in diabetic vascular complications. RESEARCH DESIGN AND METHODS Participants were from the Targeting Inflammation Using Salsalate for Type 2 Diabetes (TINSAL-T2D) study, which examined the impact of salsalate treatment on hemoglobin A1c (HbA1c) and a wide variety of other parameters. One hundred eighteen participants received salsalate, 3.5 g/day for 48 weeks, and 109 received placebo. Early glycation product levels (HbA1c and fructoselysine [measured as furosine]) and AGE levels (glyoxal and methylglyoxal hydroimidazolones [G-(1)H, MG-(1)H], carboxymethyllysine [CML], carboxyethyllysine [CEL], pentosidine) were measured in patient serum samples. RESULTS Forty-eight weeks of salsalate treatment lowered levels of HbA1c and serum furosine (P < 0.001) and CML compared with placebo. The AGEs CEL and G-(1)H and MG-(1)H levels were unchanged, whereas pentosidine levels increased more than twofold (P < 0.001). Among salsalate users, increases in adiponectin levels were associated with lower HbA1c levels during follow-up (P < 0.001). Changes in renal and inflammation factor levels were not associated with changes in levels of early or late glycation factors. Pentosidine level changes were unrelated to changes in levels of renal function, inflammation, or cytokines. CONCLUSIONS Salsalate therapy was associated with a reduction in early but not late glycation end products. There was a paradoxical increase in serum pentosidine levels suggestive of an increase in oxidative stress or decreased clearance of pentosidine precursor.

Topics: Adiponectin; Adult; Anti-Inflammatory Agents, Non-Steroidal; Arginine; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Glycated Hemoglobin; Glycation End Products, Advanced; Humans; Lysine; Male; Middle Aged; Pyruvaldehyde; Salicylates

To explore mechanisms of diabetes-associated vascular endothelial cells (ECs) injury, human umbilical vein ECs were treated for 24h with high glucose (HG; 26mM), advanced glycation end-products (AGEs; 100mug/ml) or their intermediate, glyoxal (GO: 50-5000muM). HG and AGEs had no effects on ECs morphology and inflammatory states as measured by vascular cell adhesion molecule (VCAM)-1 and cyclooxygenase (COX)-2 expressions. GO (500muM, 24h) induced cytotoxic morphological changes and protein expression of COX-2 but not VCAM-1. GO (500muM, 24h) activated ERK but not JNK, p38 or NF-kappaB. However, ERK inhibitor PD98059 was ineffective to GO-induced COX-2. While EUK134, synthetic combined superoxide dismutase/catalase mimetic, had no effect on GO-mediated inflammation, sodium nitroprusside inhibited it. The present results indicate that glyoxal, a metabolite of glucose might be a more powerful inducer for vascular ECs inflammatory injury. Nitric oxide but not anti-oxidant is preventive against GO-mediated inflammatory injury.

Topics: Antioxidants; Cullin Proteins; Cyclooxygenase 2; Diabetic Angiopathies; Endothelium, Vascular; Extracellular Signal-Regulated MAP Kinases; Flavonoids; Glucose; Glycation End Products, Advanced; Glyoxal; Humans; Nitric Oxide Donors; Organometallic Compounds; Protein Kinase Inhibitors; Salicylates; Signal Transduction; Vasculitis

The dermal microvasculature has been compared in 51 diabetics and 51 matched non-diabetic controls using tissue measurement techniques and functional assessments of blood vessel reactivity. Blood vessel walls were thicker in different groups of diabetics than the controls (p less than 0.01) but the degree of thickness did not differ between patients with insulin-dependent diabetes mellitus and those with non-insulin-dependent diabetes mellitus or between diabetics with and without vascular complications. Vascular lumina were narrower in diabetics than in controls (p less than 0.01) and diabetics with vascular complications had a greater reduction in luminal area than those without such complications (p less than 0.001) but the luminal area did not differ between the insulin-dependent and the non-insulin-dependent groups. The luminal perimeter was also reduced in the diabetic group compared to controls. The weal and flare response to intracutaneous histamine acid phosphate (50 micrograms) was markedly decreased (p less than 0.001) in diabetic subjects compared with controls, as was the response to a topically applied vasodilator (Transvasin). The degree of reduction did not differ between patients with insulin-dependent diabetes mellitus and those with the non-insulin-dependent disease but diabetics with vascular complications show impaired responses as compared to those without. The maximum increase in skin temperature on the volar surface of the right middle finger during a period of reactive hyperaemia following 3 min of cuff-induced ischaemia was also markedly decreased in diabetics compared with control subjects. It did not differ between those with insulin-dependent diabetes mellitus and those with the non-insulin-dependent disease but did between diabetics with vascular complications as compared with those without. This study confirms that the cutaneous vasculature of diabetics differs markedly from that of matched control subjects. The results also indicate that there are significant differences between diabetics with vascular complications and those without. The quantitative approaches adopted may have predictive value.

Topics: Adult; Aged; Benzocaine; Biometry; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Drug Combinations; Histamine; Humans; Hyperemia; Middle Aged; Niacin; Salicylates; Skin; Skin Temperature

Topics: Boric Acids; Diabetic Angiopathies; Female; Humans; Hypertension; Joint Diseases; Leg Ulcer; Male; Ointments; Salicylates; Varicose Ulcer; Zinc